rs372169366

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_006231.4(POLE):c.6004+5G>T variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,608,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

POLE
NM_006231.4 splice_donor_5th_base, intron

Scores

Splicing: ADA: 0.8900

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:8

Conservation

PhyloP100: 2.88

Variant links:

Genes affected

POLE (HGNC:9177): (DNA polymerase epsilon, catalytic subunit) This gene encodes the catalytic subunit of DNA polymerase epsilon. The enzyme is involved in DNA repair and chromosomal DNA replication. Mutations in this gene have been associated with colorectal cancer 12 and facial dysmorphism, immunodeficiency, livedo, and short stature. [provided by RefSeq, Sep 2013]

POLE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.29).

BP6

Variant 12-132634181-C-A is Benign according to our data. Variant chr12-132634181-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220739.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=4, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
POLE	NM_006231.4 linkuse as main transcript	c.6004+5G>T	splice_donor_5th_base_variant, intron_variant	ENST00000320574.10
POLE	XM_011534795.4 linkuse as main transcript	c.6004+5G>T	splice_donor_5th_base_variant, intron_variant
POLE	XM_011534797.4 linkuse as main transcript	c.5083+5G>T	splice_donor_5th_base_variant, intron_variant
POLE	XM_011534802.4 linkuse as main transcript	c.2992+5G>T	splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10 linkuse as main transcript	c.6004+5G>T		splice_donor_5th_base_variant, intron_variant		1	NM_006231.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000312

AC:

AN:

243762

Hom.:

AF XY:

0.000197

AC XY:

AN XY:

131698

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00696

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000551

Gnomad OTH exome

AF:

0.000669

GnomAD4 exome

AF:

0.000177

AC:

258

AN:

1456000

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

122

AN XY:

723868

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00744

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000307

Gnomad4 OTH exome

AF:

0.000548

GnomAD4 genome

AF:

0.000131

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000557

Hom.:

Bravo

AF:

0.000185

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 12, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 17, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 15, 2016	The c.6004+5G>T variant in POLE has not been previously reported in individuals with colorectal cancer but has been identified in 22/65018 of European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs372169366). This variant is located in the 5' splice region. Although nucl eotide substitutions at +5 position of the intron are relatively common causes o f aberrant splicing, computational tools do not suggest an impact to splicing. H owever, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the c.6004+5G>T variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 29, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jul 11, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 24, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2020	- -

Colorectal cancer, susceptibility to, 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 13, 2018

- -

POLE-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 24, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

Cadd

Uncertain

Dann

Benign

0.86

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.89

dbscSNV1_RF

Benign

0.71

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over